Having defined the magnitude, major new etiologies, key novel mechanisms and short-term and long-term impact of persistent and recurring diarrheal illnesses on cognitive development in a model collaboration and cohort of children born into active prospective surveillance in poor urban areas (shanty-towns) in Northeast Brazil, we now have a unique opportunity to better assign causal relationships by establishing the importance of genetic markers in defining risk, plan prevention strategies for future interventions, and build sustainable human genetic research together with environmental assessment. This proposal directly addresses potentially remediable mechanisms of long-term cognitive impairment, which we have calculated more than doubles the DALY impact of early childhood diarrheal illnesses worldwide. We postulate, based on our previous cognitive outcome data, that the greatest long-term impact will occur in children with persistent and recurring diarrheal illnesses carrying APOE4 alleles, a well-known genetic marker related to poor recovery following brain injury and sporadic, late-onset Alzheimer disease. Since APOE4 is associated with impaired recovery from brain injury, but not with cognitive function in healthy children, an association of APOE4 with impaired cognitive development that we see with heavy diarrhea burdens in favela (shanty-town) children will strongly suggest that these children endure a form of "brain injury" with their heavy diarrheal illness burdens in their most formative first two years of life. Hence, our longstanding collaboration and prospective field cohort surveillance will enable the use of new approaches and genetic technologies to define APOE allele distribution with impaired cognitive development, thus assessing the potential impact of early childhood diarrheal illnesses as a cause of "brain injury" at the critical formative first 2 years of life. This project will also open new opportunities to train both US and international scientists in highly relevant bench and field investigation, holding promise for demonstrating a key intervention targeted at the most vulnerable subset of children in greatest need.